The Paramyxoviruses infect human and animal hosts and are responsible for causing major human illnesses, as well as animal infections of significant economic consequence. The entry into cells of most Paramyxoviruses requires an attachment protein, HN, H or G, depending on the virus, and a fusion (F) glycoprotein. In this proposal will study the structure and function of the HN protein to better understand how its stalk region controls the specificity of F protein activation, thereby triggering membrane fusion. We will determine why a subset of HN proteins require a proteolytic activation step to enable receptor binding, receptor destroying and fusion promoting activities. This proposal will also focus on the study of the F glycoproteins, to gain insight into potential structural differences in the prefusion conformations across the paramyxovirus family and to better understand how neutralizing antibodies engage and inhibit F protein functions. The proposed research will provide significant new insights into how these paramyxovirus entry glycoproteins mediate infection and potentially provide new avenues for the development of antiviral therapeutics. PUBLIC HEALTH RELEVANCE: The Paramyxoviruses are a large virus family whose members are the cause of significant human morbidity and mortality. The entry of paramyxoviruses into a cell requires the fusion of viral and cellular lipid membranes. This process is carried out by the viral fusion glycoprotein (F), typically after it is activated by a viral attachment protein (HN, H or G), which binds to a host cell receptor. This research proposal focuses on furthering our understanding of both F and HN proteins and how these communicate and function in viral entry and infection. In addition, the proposed research will investigate how antibodies directed against the F protein neutralize the virus. The results of this research will have potential significance in developing novel antiviral therapeutics and vaccines.